This project proposes a methodical investigation into the mechanisms by which morphine and related narcotic analgesic agents affect motor activity of the mammalian intestine. The level of resolution ranges from studies of gross, narcotic induced movements of the bowel to the molecular mechanisms by which these changes in motility occur. Although in vivo techniques are employed, extensive use will be made of in vitro techniques, especially vascularly perfused segments of intestine isolated from dogs and cats. Special attention will be paid to the effects of morphine on endogenous substances which may mediate various components of narcotic action: 5-hydroxytryptamine, histamine, catecholamines and the prostaglandins. Conventional techniques of receptor blockade, depletion and related manuevers will be employed. The potential roles of cyclic nucleotides in regulation of intestinal motility and in responses to narcotics will be examined. The mechanisms by which tolerance develops to narcotic actions will also be investigated.